In a world of complex solutions
Why we don't have a new cure for Alzheimer's disease
Polina Loseva, N+1
A person who is diagnosed with Alzheimer's disease today can get a prescription for one of four medications. None of them is related to the cause of the disease and therefore cannot cure it. Recently, the American company Biogen requested regulatory approval for a fifth, fundamentally new drug that claims to finally attack not the symptoms, but the disease directly. But it wasn't so easy with him either. We tell you how Americans are looking for an answer in conditions when clinical trials give opposite results.
The release of a new drug on the market rarely means that the problem with the disease is solved once and for all. Every time another Ministry of Health approves another remedy for some disease - whether it's something ordinary, like a cold, or destructive, like cancer – long bidding and calculations remain behind the scenes. Which patients exactly are getting better? At what stage? In what dosage and at what reception mode? There is a continuous spectrum of options between "evidence–based effective" drugs and drugs "without proven effectiveness", on which there is no clear boundary. Every time we recognize a medicine as useless, we draw this line anew. Every time we call a medicine effective, we keep numerous "buts" in mind.
A classic example of such "buts" is modern medicines for Alzheimer's disease. Of the four drugs approved in the world, three are designed to compensate for the work of already dead neurons, and another one is trying to slow down the death of new ones. None of them can save the patient, they can only slow down neurodegeneration. Therefore, although these drugs improve the quality of life of the patient, they, in fact, have nothing to do with the treatment of the disease itself.
And over time, there are only more patients. As the average life expectancy increases and the population of developed countries ages, Alzheimer's disease begins to occur more often. Now at least 50 million people are suffering from it all over the world – and modern medicine cannot offer them any answer. In 30 years, there will already be 125 million of them, and, strictly speaking, it is unknown whether the average life expectancy will continue to increase if Alzheimer's continues to "gnaw" the upper part of this graph.
We've been waiting for a scientific breakthrough. The last of the drugs for Alzheimer's (the one that slows down the death of nerve cells) appeared 17 years ago – but it also failed to triumph. The one who can solve this problem today will receive not only the laurels of the winner (and there, who knows, maybe up to The Nobel Prize is not far away), but also a huge profit – all these tens of millions of people will "get hooked" on this medicine from the day of diagnosis until the end of life.
Hurry up – you'll make the FDA laugh
The stakes are high, the temptation is great, and in 2019, the Chinese company Green Valley Pharmaceuticals declared itself a contender for laurels.
Unlike her predecessors, she tried to approach the problem from the other end (in every sense of the word): her drug GV-971 was supposed to act not on the brain, but on the intestines. By feeding the "right" symbiont bacteria and not encouraging the "wrong" ones, the drug was supposed to reduce the amount of pro-inflammatory proteins released by them – under the influence of which the immune cells of the brain also had to "calm down" and muffle inflammation, which is considered one of the causes of Alzheimer's disease.
The GV-971, as it turned out, had several "buts" at once: the dubious reputation of the manufacturing company, the failed second phase of testing and the suspicious results of the third. This, however, did not prevent the Chinese authorities from approving the drug for limited use and allowing it to enter the market. American and European regulators were more skeptical and allowed Green Valley Pharmaceuticals except to conduct an expanded third phase of testing – let's see, they say, what you will get on our territory. The results are promised no earlier than 2024, so for now the laurels remain vacant.
The decision of the Chinese authorities looked hasty, but the stakes in this race are so high that running first may be more important than honestly going the whole distance. And they had someone to race with: in the USA there was the last of the major pharmaceutical companies that had not yet left this distance – Biogen.
A medicine that tries
Biogen's drug, aducanumab, works according to the classical principle: it is an antibody to beta-amyloid. It is assumed that the antibody will stick to beta-amyloid aggregates in tissues and provoke immune cells to destroy them – thereby clearing the nerve tissue of extracellular debris and giving the surrounding neurons a chance to survive. And although not all scientists agree that this will help, at least this medicine cannot be blamed for the fact that it is not related to the cause of the disease.
When GV-971 appeared on the market and in the headlines of scientific publications, Biogen and adukanumab were going through hard times. At the beginning of 2019, two large clinical trials of the third phase – EMERGE and ENGAGE – were in full swing, involving 1,638 and 1,647 patients at an early stage of Alzheimer's disease.
But already in March, both projects had to be stopped. Based on the data collected by that time, the researchers calculated that it is unlikely that the drug will be as effective as they thought, so there is no point in risking the health of patients. The test participants were outraged, the Biogen employees were upset, the company's shares sank, and analysts buried the hope of curing Alzheimer's disease in classical ways. And then the management of Biogen changed its mind.
In October 2019, a month before the Chinese company's attempt to cut at the finish circle, Biogen representatives said that they had carefully recalculated the data from both tests and found new grounds for optimism in them. Of course, it was not about one hundred percent effectiveness and miraculous healing, but about a significant progress on the scale from useless drugs to effective ones. It turned out that in the first study, EMERGE, the number of amyloid aggregates in the brain actually decreased in patients, and in the field of cognitive abilities, progress ranged from 15 to 87 percent (depending on the scale by which they were measured).
But with the second study, ENGAGE, it turned out to be much more difficult. Although there was significantly less amyloid in the brains of its participants over time than in the placebo group, no difference could be found in terms of cognitive abilities – external signs of neurodegeneration. Where did such a discrepancy between the two tests come from, it is difficult to say for sure – especially considering that all calculations are made after the fact.
For example, according to one hypothesis, the ENGAGE sample included more people with rapidly progressing disease. It is possible that other mechanisms are involved in this, against which aducanumab is powerless, and then the results of these patients will greatly spoil the statistics. And indeed, if we exclude such people from the sample, then the results change only in one of the branches of the ENGAGE test. This means that the sample could really turn out to be heterogeneous.
This is how the average scores on the scale of cognitive impairment in Alzheimer's disease changed among the test participants. A shift to the left is a sign of improvement, a shift to the right is a sign of deterioration. 301 – ENGAGE study, 302 – EMERGE study. Every second line corresponds to a sample from which patients with a rapidly developing disease were excluded. A sample of ENGAGE with a large dose of the drug is highlighted – in it, the exclusion of these patients significantly affects the average result.
Half a good result
Anyway, Biogen sent an application to the FDA, and together they plunged into the depths of data recalculation. It took a year – during which the newspapers managed to forget about the Chinese non-accidental breakthrough, the FDA switched to monitoring medicines and vaccines against coronavirus, and the management of Biogen brought this very coronavirus to its annual summit and caused an outbreak of at least 90 cases. But despite these obstacles, the special committee continued to recalculate the Biogen data – and in early November reported on the fruits of its reflections.
These fruits in a brief retelling look like this: "The data of the two tests of the third phase strongly differ from each other. We do not know exactly what was the reason for this – unequal samples, protocol adjustments during tests or statistical emissions – but we believe that this discrepancy is sufficient to consider these results independently of each other." In other words, according to the authors of this report, the results of both tests are equivalent and do not affect each other. That is, the very fact of the failure of aducanumab in one of the studies does not detract from the result obtained during the second – which just allows us to consider the drug effective.
Thus, the FDA committee put its own bosses before the eternal question: how to characterize a glass in which there is exactly half of the water? Can we assume that the drug works if it acts strictly in every second trial?
In the case of medicines, this dilemma is not reduced to an optimistic or pessimistic view of things. There is no answer to this question that would suit everyone at once. If it is decided that half of the successful trials of a drug are not enough to jump the bar of effectiveness, then millions of people will be left without a single chance of a cure. What if he could really help at least half of them? What if, having tried it on millions ready for everything, developers and doctors could learn how to use it better and choose a more effective dosage?
If you decide that the significance of success is more important than failure, and allow a drug with questionable effectiveness, then perhaps at first there will be fewer dissatisfied people – the public demand for victory over Alzheimer's is too strong – but the consequences may be much more serious. Doctors will start prescribing the drug to patients – and they will sue them for the fact that it does not work. Patients will start taking this medicine – and thereby deprive themselves of the chance to participate in clinical trials of new, possibly more effective therapies.
And if the ratio of successes and failures does not even out later, then the FDA will be the first organization to be criticized for drawing the line between almost useless and not quite effective in the wrong place. Exactly this is already happening with two gene therapy drugs against spinal muscular atrophy (one of which, by the way, also produces "Biogen"). A few years after they entered the market, doctors and the scientific community began to gently hint that these drugs do not seem to work as well as they were said to. And since they cost more than any other drugs on Earth, these claims are understandable – spinal muscular atrophy therapy can seriously hit the US health budget. And considering how many patients with Alzheimer's disease will immediately want to get a new Biogen drug if it enters the market, it can be assumed that the public will ask the FDA with particular rigor for it.
This is how the patients' scores on the cognitive impairment scale changed throughout the aducanumab trial. The results of the "successful" branch, EMERGE.
This is how the patients' scores on the cognitive impairment scale changed throughout the aducanumab trial. The results of the "failed" branch, ENGAGE.
The FDA found itself facing a much more serious task than the one that its Chinese colleagues were solving a year ago. The approval of GV-971 may have been an important event for Chinese patients, but it did not allow the drug to go outside the country. The zone of influence of the United States and, consequently, the FDA is much wider – and the approval of the drug in the States seriously simplifies its recognition, at least in Europe, where a significant part of the solvent aging population interested in Alzheimer's treatment lives.
When it's hard to say no
The FDA committee, which recalculated the results for Biogen, does not have the authority to make a decision. He only evaluates the quality of the data – and his assessment clearly favored Biogen and his brainchild: the committee agreed with the company that the positive result of one test remains the same regardless of what happened during the other.
A few days after the publication of the report, it was to be discussed at a meeting of external experts. And the alignment of their voices turned out to be exactly the opposite: 10 "against", only one "for".
The system of checks and balances has once again worked. The FDA has received two independent answers to a question that does not have a good solution. However, both the first and second options serve as nothing more than recommendations. The FDA promised to make a final decision in March – and he will have to be Solomon. Especially when you consider that there will be many more stories of this kind.
A few days ago, another company that deals with the therapy of another undefeated disease – amyotrophic lateral sclerosis – said that the results of its clinical trials look disappointing only at first glance. But since the company's representatives see a certain potential in them, they, following in the footsteps of Biogen, count on the support of the FDA and a thorough joint recalculation of data.
And right now, the FDA is facing the need to make a more urgent decision than for Alzheimer's or amyotrophic lateral sclerosis. Pfizer, which was the first to summarize the preliminary results of testing its anti-coronavirus vaccine, recently announced that it was already preparing documents for registration. On December 8-10, the FDA promised to make a decision – but it will hardly be easy to do this, given that the test data has not yet been published anywhere, and since the vaccination of most participants, two months have not yet passed the two months set by the FDA itself, during which researchers must make sure that the vaccine is safe.
In the case of the Biogen drug, the public demand turned out to be strong enough to swing the pendulum towards a positive decision, and inconsistencies in the data are serious enough to put it back in place. In the situation with the coronavirus vaccine, the request is much higher, the need is much more acute, and the deadlines are already pressing. Will the FDA have enough strength to resist if Pfizer's results turn out to be not as unambiguous as it seems according to their press releases?
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